The present invention provides peptides and compounds that bind the interleukin 1 receptor (IL-1R), methods for assaying interleukin 1 (IL-1), and methods for inhibiting the binding of IL-1 to the IL-1R. The invention has application in the fields of biochemistry and medicinal chemistry and particularly provides IL-1 antagonists for use in the treatment of human disease.
IL-1 is a polypeptide hormone, a cytokine, that exists in various forms, the genes for two of which, IL-1.alpha. and IL-1.beta., have been cloned. Unless otherwise noted, "IL-1" refers to either or both IL-1.alpha. and IL-1.beta.. These two genes are both located in chromosome 2; each gene contains 7 exons, and the two genes are homologous in a region of the sixth exon. Both IL-1.alpha. and IL-1.beta. initially exist as 31 kD precursors but are processed by proteases to produce the amino terminus of the 17.5 kD mature proteins. Receptors for IL-1 recognize the .alpha. and .beta. forms, and both forms have similar biological properties. See Dinarello (1991) Blood 77 (8):1627-1652, incorporated herein by reference.
The biological properties of IL-1 include mediating many immunological and inflammatory responses to infection and tissue injury. Because of the role of IL-1 in these important processes, the therapeutic benefits of IL-1 and derivatives of IL-1 have been extensively studied. See U.S. Pat. Nos. 5,075,288 and 5,077,219, incorporated herein by reference. Inappropriate production or response to IL-1 plays a role in many chronic inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, psoriasis, inflammatory bowel disease, encephalitis, glomerulonephritis, and respiratory distress syndrome. See Bender and Lee (1989) Ann. Rep. Med. Chem. 25:185-193; and U.S. Pat. No. 5,075,222, particularly columns 1 to 3, each of which is incorporated herein by reference.
Because of the important biological properties of IL-1, IL-1 inhibitors have been extensively studied, as reviewed in Larrick (1989) Immunol. Today 10 (2):61-66, incorporated herein by reference. IL-1 inhibitors include the naturally occurring IL-1ra protein and soluble IL-1 receptor, as well as derivatives of IL-1.alpha. and IL-1.beta. produced by recombinant DNA technology, as discussed in Dinarello, supra. See also PCT patent publication Nos. 91/08285, published Jun. 13, 1991, and 91/02127, published Nov. 14, 1991, incorporated herein by reference.
In similar fashion, scientists have studied the IL-1R, as reviewed in Dower and Urdal (1987) Immunol. Today 8 (2):46-51, incorporated herein by reference. Two distinct naturally occurring types of the IL-1R are known to exist, and the corresponding genes have been cloned and expressed, as reported in Dower et al., (1990) J. Clin. Immunol. 10 (6):289-299; PCT patent publication No. 91/00742; U.S. Pat. No. 4,968,607, and McMahon et al.,(1991) EMBO J. 10 (10):2821-2832, each of which is incorporated herein by reference. The type I receptor (IL-1RtI) is 80 kD in size, while the type II receptor (IL-1RtII) is 60 kD in size. A number of studies regarding whether IL-1RtI and IL-1RtII have different affinities for ligands have been conducted; see Slack et al. (1993) J. Biol. Chem. 268:2513-2524 and Hannum et al., (1990) Nature 343:336-340.
The availability of cloned genes for IL-1RtI and IL1RtII, including a soluble IL-1RtI derivative, facilitates the search for agonists and antagonists of these important receptors. The availability of the recombinant receptor protein allows the study of receptor-ligand interaction in a variety of random and semi-random peptide diversity generation systems. These systems include the "peptides on plasmids" system described in U.S. Pat. No. 5,270,170, the "peptides on phage" system described in U.S. patent application Ser. No. 718,577, filed Jun. 20, 1991, now U.S. Pat. No. 5,432,018, and in Cwirla et al., (1990) Proc. Natl. Acad. Sci. USA 87:6378-6382, and the "very large scale immobilized polymer synthesis" system described in U.S. Pat. No. 5,143,854; PCT patent publication No. 90/15070, published Dec. 13, 1990; U.S. patent application Ser. No. 624,120, filed Dec. 6, 1990; Fodor et al., Feb. 15, 1991, Science 251:767-773; Dower and Fodor (1991) Ann. Rep. Med. Chem. 26 :271-180; and U.S. patent application Ser. No. 805,727, filed Dec. 6, 1991now U.S. Pat. No. 5424,768; each of the foregoing patent applications and publications is incorporated herein by reference.
There remains a need, however, for compounds that bind to or otherwise interact with the IL-1R, both for studies of the important biological activities mediated by this receptor and for treatment of disease. The present invention provides such compounds.